Our working hypothesis is that a polymorphism exists for a gene or genes that influence telomerase expression. In the majority of humans, there is tight control of telomerase, and post-natally in most tissues, it is completely suppressed or is maintained at levels insufficient to maintain telomeres, as in the case of the hematopoietic stem cell. With aging, particularly with superimposed myelosuppressive insults, critical telomere shortening leads to cytogenetic instability, stem cell apoptosis, and impaired hematopoiesis. In a subgroup of individuals telomerase can be upregulated to a level sufficient to elongate telomeres. If this occurs in steady state hematopoiesis then proliferative senescence, cytogenetic instability and impaired hematopoiesis would not occur and the gene(s) would protect against the risk of cancer linked to cytogenetic instability. If the telomerase in upregulated only in stressed situations, it would not prevent critical telomere shortening but would be capable of preventing death of cells in crisis including those with cytogenetic instability, and by permitting survival of such cells, favoring the stabilization and immortalization of malignant clones. Our first objective is to develop an in vitro system for identification of "telomere elongating" versus "shortening" individuals. We shall expose human hematopoietic stem cells (CD34+ or CD34+, CD38-ve) at limiting dilutions in vitro to the proliferative stress that exists in vivo, particularly in aging individuals who receive chemotherapy and transplantation. By measuring telomere loss or gain over 3-5 weeks in vitro an assay for "telomere elongation" phenotype can be developed. This will be applied to a study of normal aging individuals to evaluate the frequency of "telomere elongators" in a population without cancer, and thus to determine whether there is selection for or against this feature in association with aging or development of cancer. Secondly, we shall compare the frequency in our myeloma population to other hematopoietic malignancies (chronic lymphoid and myeloid leukemias), and a non-hematopoietic malignancy (prostate cancer). We shall determine if the "telomere elongation" individual has improved stem cell function, particularly in old age. This will be measured using stromal co-cultures that support long term stem cell proliferation and progenitor cell expansion, and by xenografting isolated CD34+ cells into NOD/SCID mice.